U.S. patent application number 10/477776 was filed with the patent office on 2004-11-04 for process for the preparation of imipenem.
Invention is credited to Kumar, Yatendra, Rai, Bishwa Prakash, Tewari, Neera.
Application Number | 20040220168 10/477776 |
Document ID | / |
Family ID | 11097061 |
Filed Date | 2004-11-04 |
United States Patent
Application |
20040220168 |
Kind Code |
A1 |
Kumar, Yatendra ; et
al. |
November 4, 2004 |
Process for the preparation of imipenem
Abstract
The present invention relates to an improved, cost effective and
industrially advantageous process for the preparation of
imipenem.
Inventors: |
Kumar, Yatendra; (Haryana,
IN) ; Tewari, Neera; (Haryana, IN) ; Rai,
Bishwa Prakash; (Uttar Pradesh, IN) |
Correspondence
Address: |
Jayadeep R Deshmukh
Ranbaxy Pharmaceuticals Inc
Suite 2100
600 College Road East
Princeton
NJ
08540
US
|
Family ID: |
11097061 |
Appl. No.: |
10/477776 |
Filed: |
June 16, 2004 |
PCT Filed: |
May 15, 2002 |
PCT NO: |
PCT/IB02/01670 |
Current U.S.
Class: |
514/210.1 ;
540/350 |
Current CPC
Class: |
C07D 477/02 20130101;
C07D 477/20 20130101; Y02P 20/55 20151101; A61P 31/04 20180101 |
Class at
Publication: |
514/210.1 ;
540/350 |
International
Class: |
A61K 031/407; C07D
487/04 |
Foreign Application Data
Date |
Code |
Application Number |
May 18, 2001 |
IN |
594/DEL/01 |
Claims
We claim:
1. A process for the preparation of imipenem of Formula I
10comprising: a) activating a keto ester compound of Formula II,
11wherein R is a protecting group with a phosphorohalidate of
Formula VI 12wherein X is a halogen atom and R' is aryl, in the
presence of a base and a catalytic amount of a dialkylaminopyridine
to obtain enolphosphate compound of Formula III, 13wherein R and R'
have the same meaning as defined above, b) reacting the enol
phosphate intermediate of Formula III, in situ with
2-aminoethanethiol or an acid addition salt thereof to get
thienamycin ester of Formula IV, 14wherein R has the same meaning
as defined above, c) reacting thienamycin ester of Formula IV in
situ with benzyl formimidate or an acid addition salt thereof in
the presence of a base to get carboxyl protected imipenem of
Formula V, 15wherein R has the same meaning as defined above, and
d) hydrogenating the carboxyl protected imipenem of formula V in an
aqueous medium to obtain imipenem.
2. The process of claim 1 wherein the dialkylaminopyridine is
4-(dimethylamino)pyridine.
3. The process of claim 1 wherein the base used at step a) and step
c) is a secondary amine or a tertiary amine.
4. The process of claim 3 wherein said base is selected from the
group consisting of diisopropylamine, dicyclohexylamine,
2,2,6,6-tetramethyl ethylpiperidine (TMP),
1,1,3,3-tetramethylguanidine(TMG), diisopropylethylamine,
triethylamine, tributylamine, and mixture(s) thereof.
5. The process of claim 1 wherein the protecting group R is benzyl,
p-nitrobenzyl or methoxymethyl in the compound of Formula II.
6. The process of claim 1 wherein the reaction at step a) is
performed in an organic solvent.
7. The process of claim 6 wherein said organic solvent is selected
from the group consisting of N,N-dimethylacetamide,
N,N-dimethylformamide, N-methylpyrrolidone, ethyl acetate,
dichloromethane, tetrahydrofuran, and mixture(s) thereof.
8. The process of claim 6 wherein the reaction at step a) is
performed in a mixture of dichloromethane and one of the solvents
selected from N,N-dimethylacetamide, N, N-dimethyl formamide and
N-methylpyrrolidone.
9. The process of claim 1 wherein the reaction at step b) is
performed at a temperature of from about -60 to -75.degree. C.
10. The process of claim 1 wherein R' is phenyl in the compound of
Formula III.
11. The process of claim 1 wherein the hydrogenation at step d) is
carried out in an aqueous medium comprising a mixture of water and
a lower alcohol.
12. The process of claim 11 wherein the lower alcohol is selected
from the group consisting of methanol, ehtanol, isopropanol, and
propanol.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to an improved, cost effective
and industrially advantageous process for the preparation of
imipenem.
BACKGROUND OF THE INVENTION
[0002] Imipenem monohydrate of Formula I which is the N-formimidoyl
derivative of thienamycin and has the structural Formula I. 1
[0003] It is the first clinically available member of a new class
of .beta.-lactam antibiotics that possess the carbapenem ring
system. Imipenem exhibits an extremely broad spectrum of activity
against gram-positive and gram-negative aerobic and anaerobic
species, which is partly due to its high stability in the presence
of .beta.-lactamases.
[0004] Imipenem was first disclosed in U.S. Pat. No. 4,194,047.
Several general methods for the preparation of N-methylene
derivatives of thienamycin including imipenem have been outlined in
U.S. Pat. No. 4,194,047 starting from thienamycin. The process for
the preparation of imipenem has been found to give the product in
low yield and of poor quality due to inherent instability of the
starting compound i.e. thienamycin.
[0005] U.S. Pat. No. 4,292,436 provides an alternate method for the
preparation of imipenem from bicyclo ketone precursor of Formula
II, 2
[0006] wherein R is a protecting group, comprising activating the
keto ester and reacting the activated keto ester with
N-formimidoyl-2-aminoeth- anethiol to obtain carboxyl protected
imipenem which gives imipenem after hydrogenation. However, the
process gives low yields of the final product (59% in solution and
35% of isolated imipenem monohydrate).
[0007] U.S. Pat. No. 4,374,772 gives an improved process for
preparing imipenem from dilute aqueous solutions of thienamycin
using benzylic formimidate reagents. However, the process has the
disadvantage of producing at least 5% of dimer bis-thienamycin
formamidene along with the desired proudct imipenem.
[0008] U.S. Pat. No. 4,894,450 uses new reagents--bis
(chloro-substituted phenyl) phosphorochloridate to activate the
bicycloketone precursor of formula 11, wherein R is a protecting
group. Subsequent reaction with cysteamine hydrochloride, amidine
formation and hydrogenolysis of the ester group gives good yield of
imipenem. However, the reagent employed for activation is not
available commercially and its preparation involves a cumbersome
multistage purification process.
[0009] In light of the above drawbacks in the prior art processes,
there is a need for the development of a process for the
preparation of imipenem which is convenient to operate on an
industrial scale, employs readily and commercially available raw
materials and reagents and which process gives substantially pure
product in good yield.
SUMMARY OF THE INVENTION
[0010] It is an object of the present invention to solve the
problems associated with the prior art and provide an efficient
process. The process provides obvious benefits with respect to
economics and convenience to operate on a commercial scale.
[0011] Accordingly, the present invention relates to an improved
process for the preparation of imipenem of sufficient purity and
high yield starting from the bicyclo ketone precursor of formula
II, wherein R is a protecting group.
[0012] In particular, the present invention relates to a process
for the preparation of imipenem of Formula I 3
[0013] comprising:
[0014] a) activating a keto ester compound of Formula II, 4
[0015] wherein R is a protecting group,
[0016] with a phosphorohalidate derivative of Formula VI, 5
[0017] wherein X is a halogen atom and R' is aryl,
[0018] in the presence of a base and a catalytic amount of a
dialkylaminopyridine, to obtain enol phosphate compound of Formula
III, 6
[0019] wherein R and R' have the same meaning as defined above,
[0020] b) reacting the enol phosphate intermediate of Formula III,
in situ with 2-aminoethanethiol or an acid addition salt thereof to
get thienamycin ester of Formula IV, 7
[0021] wherein R has the same meaning as defined above,
[0022] c) reacting thienamycin ester of Formula IV in situ with
benzyl formimidate or an acid addition salt thereof in the presence
of a base to get carboxyl protected imipenem of Formula V, 8
[0023] wherein R has the same meaning as defined above, and
[0024] d) hydrogenating the carboxyl protected imipenem of formula
V in an aqueous medium to obtain imipenem.
[0025] The reactions at steps a) and c) are preformed in the
presence of a base which may be a secondary amine or a tertiary
amine. Examples of secondary amines include diisopropylamine,
dicyclohexylamine, 2,2,6,6-tetramethylethylpiperidine (TMP) and
1,1,3,3-tetramethylguanidine (TMG).
[0026] Examples of suitable tertiary amines include
diisopropylethylamine, triethylamine and tributylamine.
[0027] The presence of a catalytic amount of dialkylaminopyridine
at step a) prevents the formation of impurity of formula VII, 9
[0028] The impurity of Formula VII is formed in substantial
quantities (14-15% by HPLC) by side reaction of the hydroxymethyl
group at the 6-position of the carbapenem.
[0029] Dialkylaminopyridines are used in catalytic amounts,
preferably in the range of about 0.5 to 2% w/w relative to the keto
ester of Formula II. For the purpose of the present invention,
dialkylaminopyridine includes pyridine substituted at the 2- or
4-position. Examples of such dialkylamino substituents include
N,N-dimethylamino, N,N-diethylamino, N,N-dicyclohexylamino,
N-cyclohexyl-N-methylamino, 1-pyrrolidinyl, 1-piperidinyl and
mixture(s) thereof.
[0030] The protecting group R in the compound of Formula II is any
carboxylic acid protecting group which may be easily removed by
hydrogenation, such as benzyl, p-nitrobenzyl or methoxymethyl.
[0031] In the compound of Formula VI, X is a halogen atom which may
be chloro, bromo or iodo. Particularly preferred is chloro. R' in
the compound of Formula VI is aryl, preferably phenyl, which may be
substituted.
[0032] Compounds of Formula II, VI and benzylformimidate or its
acid addition salts may be obtained by methods known in the
art.
[0033] The reaction at step a) is carried out in an organic solvent
such as N, N-dimethyl acetamide (DMAc), N,N-dimethylformamide
(DMF), N-methylpyrrolidone (NMP), ethylacetate, dichloromethane,
tetrahydrofuran, or mixture(s) thereof. Preferably a mixture of
dichloromethane and any of the solvents chosen from DMAc, DMF or
NMP is used. The reaction at step b) is carried out at a
temperature of from about -50 to -75.degree. C., preferably at
about -60 to -75.degree. C.
[0034] Steps a), b) and c) are performed in situ, thus the solvent
and the base are common to the three steps. Additional amount of
the base is added to facilitate the reaction at step c).
[0035] Acid addition salts of 2-aminoethanethiol and
benzylformimidate used at steps b) and c) respectively may be the
same or different and may arise from either organic or inorganic
acids. Examples of such salts include hydrochloride, hydrobromide,
hydroiodide, sulfate, methanesulfonate, benzenesulfonate, fumarate,
tartrate, thiocyanate, tosylate, phosphate, picrate, succinate,
pivalate, benzoate, acetate and citrate salts. Particularly
preferred are the hydrochloride salts of both 2-aminoethanethiol
and benzylformimidate.
[0036] The hydrogenation step d) is carried out after suitable
aqueous work up of the reaction mixture from step c). Preferably, a
lower alcohol is added to the obtained aqueous solution of compound
V and hydrogenation carried out at a pH of about 7 to 8 in the
presence of N-methylmorpholine buffer. Examples of lower alcohols
which may be added include methanol, ethanol, isopropanol and
propanol. The hydrogenation may be carried out using any of the
metal cataylsts such as platinum oxide, platinum/carbon, palladium
hydroxide and palladium/carbon.
[0037] Imipenem is obtained as a solution after hydrogenation and
filtration of the catalyst. Imipenem may then be isolated from the
solution in the usual manner by lyophilization and/or
crystallization methods known in the art but is preferably
crystallized by the method described in the patent application
filed concurrently herewith.
DETAILED DESCRIPTION OF THE INVENTION
[0038] In the following section one preferred embodiment is
described by way of example to illustrate the process of the
invention. However, it is not intended in any way to limit the
scope of the present invention.
PREPARATION OF IMIPENEM
EXAMPLE 1
[0039] Step a)--Preparation of Enol Phosphate Intermediate
[0040] A solution of p-nitrobenzyl (3R, 5R, 6S)-2oxo-6-[(1
R)-1-hydroxyethyl)] carbapenem-3-carboxylate (30 g) was dissolved
in a mixture of N, N-dimethylacetamide (300 ml) and dichloromethane
(150 ml). The solution was cooled to -55.degree. C. and
4-(dimethylamino)pyridine (0.17 g) was added followed by
diisopropylethylamine (26.7 g). The mixture was stirred for 5 min.
at -55.degree. C. and then a solution of diphenylchlorophosphate
(25.4 g) in dichloromethane (30 ml) was added dropwise at -55 to
-45.degree. C. The reaction mixture thus obtained was stirred
further for 30 minutes to obtain the enol phosphate ester.
[0041] Step b)--Preparation of Thienamycin Ester
[0042] The reaction mixture from step a) was further cooled to -70
to -75.degree. C. and a solution of 2-aminoethanethiol
hydrochloride (12 g) in N,N-dimethylacetamide (60 ml) was added in
10 min at -75 to -60.degree. C. The reaction mixture was stirred
for another 60 min. to produce p-nitrobenzyl ester of
thienamycin.
[0043] Step c)--Preparation of p-Nitrobenzyl Ester of Imipenem
[0044] To the above reaction mixture from step b), was added
diisopropylethylamine (16.0 g) and benzyl formimidate hydrochloride
(20.0 g) at -50 to -55.degree. C. The reaction mixture was
maintained for about one and a half hour at the same temperature.
The temperature was then raised to -20.degree. C. in 20-30 min and
the reaction mixture stirred for 20-30 min at this temperature to
obtain the imipenem ester.
[0045] Step d)--Preparation of Imipenem
[0046] The above clear solution of step c) was poured into a
mixture of water (300 ml), isopropanol (150 ml) and
N-methylmorpholine (26 g) maintained at 5-10.degree. C. and the pH
of the solution adjusted to 7.0 to 7.5. The solution was
hydrogenated at 3-4 kg pressure for 2.5 hour at 10-25.degree. C.
over palladium/carbon. The mixture was filtered and assayed for
imipenem (80%, as determined by HPLC).
[0047] While the present invention has been described in terms of
its specific embodiments, certain modifications and equivalents
will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
* * * * *